Like neurons, the cardiac myocyte appears to be especially susceptible to protein aggregation with aging and during disease states such as heart failure. The unfolded protein response and endoplasmic reticulum (ER) stress pathways appear to be uniquely regulated in the heart, possibly because of how this celltype has to deal with production of large sarcomeric proteins and the production and continual remodeling of an elaborate extracellular matrix (ECM), with synthesis of many large extracellular proteins. In the past funding cycle of this award we identified thrombospondins, which comprise a family of 5 genes (Thbs1-5) and are calcium binding matracellular proteins, as critical regulators of the ER stress response in the heart. Here we propose the hypothesis that thrombospondin proteins are intracellular regulators of an adaptive ER stress response that protects the heart from injury or protein aggregation-based disease. We further hypothesize that thrombospondin3/4 genes are exclusively cardioprotective while thrombospondin1/2 have both adaptive and maladaptive functional domains. To address these hypotheses we propose 2 specific aims. Aim #1 will examine the function of all 5 thrombospondin genes in the heart, both by transgenesis to overexpress each, as well as in gene-targeted mice in which multiple family members are deleted. Aim #2 will examine the intracellular mechanisms whereby thrombospondin proteins provide protection as either due to ATF6a activity or a more general chaperone activity associated with large ECM proteins and other secreted proteins. The overall paradigm that these aims should help establish; that being a critical or primordial function for thrombospondins as intra-vesicular regulators in the ER compartment and Golgi, would be completely novel and hence innovative. The results would also suggest new molecular targets for exploitation in treating select forms of heart disease.